Cromoglycic acid derivatives, method of production thereof and pharmaceutical composition

ABSTRACT

Cromoglycic acid derivatives of the general formula ##STR1## wherein R 1  is an α-, β- or γ-amino acid residue (for ester bonding) whose amino group may optionally be substituted by at least one lower alkyl group, and R 2  and R 3  each independently is a lower alkyloxy-substituted or an unsubstituted lower alkyl group, an 1-alkanoyloxyalkyl group, an 1-alkoxycarbonyloxyalkyl group, a phthalidyl group or a 5-methyl-1,3-dioxol-2-on-4-ylmethyl group; nontoxic salts thereof; and pharmaceutical compositions containing such compounds. Since the compounds have antiallergic activity and are readily absorbable into the blood stream, they are useful as oral antiallergic agents.

FIELD OF ART

This invention relates to cromoglycic acid derivatives and nontoxicsalts thereof and pharmaceutical compositions, for example antiallergiccompositions, containing the same.

BACKGROUND ART

So far, the compound of formula (II): ##STR2## [hereinafter sometimesreferred to as "cromoglycic acid (II)"], which has antiallergicactivity, has been used as an antiallergic agent generally in its sodiumsalt form.

Since it cannot be absorbed in the digestive tract, cromoglycic acid(II) has been administered generally by spraying for inhalation into thenostrils or oral cavity using a sprayer for exclusive use for thatpurpose.

However, this method of administration is disadvantageous in thatdifficulties in connection with the operation of the sprayer areencountered in the process of inhalation (especially in young childrenand the aged).

Therefore, development of cromoglycic acid derivatives absorbable evenafter oral administration has been earnestly desired.

Accordingly, it is a primary object of the invention to providecromoglycic acid derivatives which are orally administrable and havehigh antiallergic activity.

A second object of the invention is to provide a method of producing thenoted derivatives.

A third object of the invention is to provide pharmaceuticalcompositions, for example antiallergic compositions for oralapplication, which contain said compounds.

DISCLOSURE OF THE INVENTION

As a result of their investigation in search of orally administrable,novel cromoglycic acid derivatives, the present inventors found that thecromoglycic acid derivatives (I) defined hereinbelow are superior inabsorbability through the digestive tract and, after absorption, arerapidly converted to the cromoglycic acids (II) (hereinafter sometimesreferred to as "non-ester forms") as a result of in vivo enzymatichydrolysis of the respective ester moieties, which means that oraladministration of the cromoglycic acid derivatives (I) results in highblood levels of the non-ester forms which have excellent antiallergicactivity, and hence results in prolonged maintenance of saidantiallergic activity. The present inventors also found that conversionof the cromoglycic acid derivatives (I) to their acid addition saltsincreases the efficiency of absorption and at the same time contributesto the stabilization of the cromoglycic acid derivatives (I) andfacilitates the isolation procedure and the manufacture of orallyadministrable preparations. Furthermore, they found that oraladministration of the cromoglycic acid derivatives (I) in the presenceof an organic acid results in substantial increases in the solubility ofthe cromoglycic acid derivatives (I) in the digestive tract. The abovefindings and the establishment of a method of producing the cromoglycicacid derivatives (I) have now led to completion of the presentinvention.

Thus, the present invention relates to compounds of the general formula(I) [i.e. cromoglycic acid derivatives (I)]: ##STR3## wherein R¹ is anα-, β- or γ-amino acid residue (for ester bonding) whose amino group mayoptionally be substituted by at least one lower alkyl group, and each ofR² and R³ is, independently, a lower alkyloxy-substituted or anunsubstituted lower alkyl group, a 1-alkanoyloxyalkyl group, a1-alkoxycarbonyloxyalkyl group, a phthalidyl group or a5-methyl-1,3-dioxol-2-on-4-ylmethyl group and nontoxic salts thereof.

The invention also relates to a method of producing the cromoglycic acidderivatives (I) which comprises reacting a compound of the generalformula (III) with a compound of the general formula (IV) givenhereinbelow.

The invention further relates to antiallergic agents which contain thecromoglycic acid derivatives (I) or nontoxic salts thereof as activeingredients.

Referring to R¹ in general formula (I), the amino acid residue forms anester bond with the adjacent oxygen atom and is an α-, β- or γ-aminoacid residue. The amino group of said amino acid residue may optionallybe substituted by at least one lower alkyl, for example a C₁₋₄ loweralkyl, such as methyl, ethyl, propyl, iso-propyl or butyl. Such aminoacid residue may be in the D, L or DL form and further may be in theform of a peptide composed of two or more amino acids. Examples of suchamino acid residues are as follows:

Neutral amino acid residues:

Aliphatic amino acid residues [glycyl, alanyl, valyl, leucyl, isoleucyl,etc.], hydroxyamino acid residues [seryl, threonyl, etc.],sulfur-containing amino acid residues [cysteinyl, cystyl, methionyl,etc.], amidoamino acid residues [asparaginyl, glutaminyl, etc.],aromatic amino acid residues [phenylalanyl, tyrosyl, tryptophyl, etc.],and so on;

Acidic amino acid residues:

Aspartyl, glutamyl, etc.;

Basic amino acid residues:

Histidyl, lysyl, arginyl, etc.;

Imino acid residues:

Prolyl, hydroxyprolyl, etc.;

Amino acid residues other than α-amino acid residues:

β-Alanyl, γ-aminobutyryl, etc.;

N-substituted amino acid residues:

Sarcosyl, N,N-dimethylglycyl, etc.; and

Peptide residues:

Glycylglycyl, alanylglycyl, leucylglycyl, etc.

Referring to R² and R³ in general formula (I), the term "lower alkyl"means a straight or branched alkyl group containing 1-6 carbon atoms,such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl or n-hexyl.

The alkanoyl moiety of the 1-alkanoyloxyalkyl group represented by R²and/or R³ contains 1-10 carbon atoms, preferably 1-7 carbon atoms, andthe alkyl moiety contains 1-4 carbon atoms, preferably 1-2 carbon atoms.As such group, there may be mentioned, for example, acetoxymethyl,propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl,pivaloyloxymethyl, n-valeryloxymethyl, 2-methylbutynyloxymethyl,isovaleryloxymethyl, n-hexanoyloxymethyl, 3-methylvaleryloxymethyl,neohexanoyloxymethyl, 2-methylhexanoyloxymethyl,2,2-dimethylbutyryloxymethyl, diethylacetoxymethyl,dipropylacetoxymethyl, 2,2-dimethylvaleryloxymethyl,neoheptanoyloxymethyl, cyclohexanoyloxymethyl, cyclohexylacetoxymethyl,1-acetoxyethyl, 1-n-propionyloxyethyl, 1-n-butyryloxyethyl,1-isobutyryloxyethyl, 1-n-valeryloxyethyl, 1-pivaloyloxyethyl,1-isovaleryloxyethyl, 1-n-hexanoyloxyethyl and 1-cyclohexanoyloxyethyl.

The alkoxy moiety of the alkoxycarbonyloxyalkyl group represented by R²and/or R³ contains 1-10 carbon atoms, preferably 1-7 carbon atoms, andthe alkyl moiety contains 1-3 carbon atoms, preferably 2 carbon atoms.As such group, there may be mentioned, for example,1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl,1-n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl,1-n-butoxycarbonyloxyethyl, 1-tert-butoxycarbonyloxyethyl,1-pentyloxycarbonyloxyethyl and 1-hexyloxycarbonyloxyethyl.

As examples of R² and R³ which are preferable, there may be mentionedmethyl, ethyl, propyl, isopropyl, ethoxyethyl, ethoxymethyl,pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1-n-propionyloxyethyl,1-ethoxycarbonyloxyethyl and 5-methyl-1,3-dioxol-2-on-4-ylmethyl.

The cromoglycic acid derivatives (I) are preferably in the form of acidaddition salts (nontoxic salts) at the amino acid residue thereof. Anyof those acids which are capable of forming salts with the amino acidresidue moiety and are pharmaceutically acceptable may be used as thesalt for forming such acid addition salts without any particularlimitations. Examples of such acid are inorganic acids, such ashydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, andorganic acids, such as oxalic acid, fumaric acid, maleic acid, citricacid, tartaric acid, methanesulfonic acid and toluenesulfonic acid.Conversion to such salts results in further improvement in absorbabilitythrough the digestive tract and facilitation of dosage form preparation.

The cromoglycic acid derivatives (I) according to the present inventioncan be produced in the following manner, for instance:

A compound (III) of the general formula (III): ##STR4## wherein R² andR³ are as previously defined, is reacted with a compound (IV) of thegeneral formula (IV):

    R.sup.1 OH                                                 (IV)

wherein R¹ is as defined above.

The compound (IV) is subjected to the above reaction either in the formof a free carboxylic acid or in the form of a reactive derivativethereof. Thus, said compound is subjected to the acylation in the formof a free acid or a salt thereof with sodium, potassium, calcium,triethylamine, pyridine or the like, or in the form of a reactivederivative thereof, such as an acid halide (acid chloride, acid bromide,etc.), an acid anhydride, a mixed acid anhydride [with a substitutedphosphoric acid (dialkylphosphoric acid, etc.), an alkylcarbonic acid(monoethylcarbonic acid, etc.)], an active amide (amide with imidazoleor the like) or an ester (cyanomethyl ester, 4-nitrophenyl ester, or thelike).

When the compound (IV) is used in the form of a free acid, it ispreferable to use an appropriate condensing agent. Usable as thecondensing agent are, for example, dehydrating agents, such asN,N'-substituted carbodiimides (e.g. N,N'-dicyclohexylcarbodiimide) andazolide compounds (e.g. N,N-carbonyldiimidazole andN,N'-thionyldiimidazole). When these condensing agents are used, thereaction presumably proceeds via a reactive derivative of the carboxylicacid. In carrying out this reaction, the use of a base, such as4-dimethylaminopyridine, as a catalyst is preferable.

When the amino group in the compound (IV) to be subjected to the abovereaction is a primary or secondary one, this amino group shouldpreferably be protected by an amino-protecting group, such as2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl,t-butoxycarbonyl, chloroacetyl or trityl.

This reaction is generally carried out in an inert solvent. As specificexamples of the solvent, there may be mentioned water, organic solvents,such as acetone, dioxane, acetonitrile, chloroform, benzene, methylenechloride, ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide and pyridine, and mixtures of these.

The compound (III) can be produced from cromoglycic acid (II), which isa known compound, in the following manner:

A cromoglycic acid salt (salt with an alkali metal or alkaline earthmetal, such as lithium, sodium, potassium or cesium, or salt with anorganic amine, such as trimethylamine, triethylamine or pyridine) isreacted with a compound (V) of the general formula

    R--X                                                       (V)

wherein R is the same as R² or R³ and X is a group reactive with thecarbonyl group, in a polar solvent, such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide or hexamethylphosphoramide, atroom temperature to 100° C.

In place of said cromoglycic acid salt, cromoglycic acid may besubjected to the reaction in the presence of an alkali metal salt ofcarbonic acid (e.g. sodium hydrogen carbonate, potassium carbonate), analkaline earth metal salt of carbonic acid (e.g. cesium carbonate) or analkali metal or alkaline earth metal salt of a lower alkanoic acid (e.g.acetic acid).

This reaction may also be carried out in a bilayer system composed of anorganic solvent, such as chloroform or methylene chloride, and water inthe presence of a catalitic amount of a quarternary ammonium chloride(e.g. a phase transfer catalyst such as benzyltributylammoniumchloride).

As the group reactive with the carboxyl group as represented by X ingeneral formula (V), there may be mentioned halogen atoms, such as Cl,Br and I, methyl- and tolyl-sulfonate, and so on.

When the cromoglycic acid derivatives (I) obtained are in the free baseform, they may be converted to nontoxic acid addition salts by a per seknown means.

The thus-produced cromoglycic acid derivatives (I) or nontoxic saltsthereof are formulated into pharmaceutical compositions for use, forexample, as antiallergic drugs for oral administration by mixingtherapeutically effective amounts of said compounds withpharmaceutically acceptable additives, such as excipients.

Examples of the excipients are starch, lactose, sucrose, calciumcarbonate and calcium phosphate.

Meanwhile, it is preferable to further add an organic acid topharmaceutical compositions like said antiallergic drugs for oraladministration. Thus the solubility of the cromoglycic acid derivativesin the digestive tract is increased and their absorbability into theblood after oral administration is facilitated. Any of those organicacids which are pharmaceutically acceptable can be used without anyparticular limitation and, as preferred examples, there may be mentionedorganic carbocylic acids such as maleic acid, fumaric acid, tartaricacid, citric acid, succinic acid, malic acid, oxalic acid, mandelicacid, malonic acid and benzoic acid. Such organic acids are addedgenerally in an amount of 0.01-20 moles, preferably in an amount of 1-10moles, per mole of cromoglycic acid derivative (I).

Other additives may further be incorporated in said pharmaceuticalcompositions, as desired. Preferred examples of the additives are, forexample, binders (e.g. starch, gum arabic, carboxymethylcellulose,hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g.magnesium stearate, talc, etc.) and disintergants (e.g.carboxymethylcellulose calcium, talc, etc.). After admixing of theingredients, the mixture can be made up into dosage forms suited fororal administration, such as capsules, tablets, fine granules, granulesand dry syrups, by a per se known means.

The cromoglycic acid derivatives (I) and nontoxic salts thereofaccording to the present invention are used, in the same manner ascromoglycic acid (II), as oral antiallergic agents for treating allergicdiseases, such as bronchial asthma, allergic rhinitis, irritablepharyngolarynx, spring catarrh and chronic allergic conjunctivitis.

In administering them orally, a daily dose is desirably administeredorally in a single or divided doses. The daily dose may vary dependingon the state of disease, age, body weight and other factors. For theiruse as oral antiallergic agents in human adults, 1-500 mg can beadministered in 1-4 divided doses per day.

The following working examples and test examples illustrate the presentinvention in further detail but are by no means limitative of theinvention.

The following abbreviations are used hereinafter:

DSCG: Disodium cromoglycate

DMF: Dimethylformamide

DCC: N,N'-Dicyclohexylcarbodiimide

DMSO: Dimethyl sulfoxide

BOC: t-Butoxycarbonyl

EXAMPLE 1 Synthesis of diethyl L-lysylcromoglycate dihydrochloride

(1) Diethyl cromoglycate (524 mg), 520 mg of di-BOC-L-lysine and 61 mgof dimethylaminopyridine are added to 10 ml of methylene chloride. DCC(310 mg) is added at 0° C. and the mixture is stirred at thattemperature for 30 minutes, and then stirred at room temperature for 6hours. After the precipitate urea compound is filtered off, the filtrateis concentrated and purified by silica gel column chromatography to give580 mg of diethyl di-BOC-L-lysylcromoglycate (yield 68%).

IR (KBr, cm⁻¹) 1740, 1710, 1690, 1655

NMR (CDCl₃, δ ppm): 1.41 (18H, s, --C(CH₃)₃); 1.41 (6H, t, J=7 Hz, --CH₂CH₃); 1.4˜2.1 (6H, m, --(CH₂)₃ --); 2.8˜3.3 (2H, m, --CH₂ NH--); 3.9˜4.4(1H, m, ##STR5## 4.43 (4H, q, J=7 Hz, --CH₂ CH₃); 4.3˜4.8 (4H, m,##STR6## 4.7˜5.5 (2H, m, --NH--); 5.4˜5.9 (1H, m ##STR7## 6.87 (2H, s,--H in position 3 of chromone nucleus); 6.8˜7.4 (4H, m, --H in position6 and in position 8 of chromone nucleus); 7.58 (2H, t, J=9 Hz, --H inposition 7 of chromone nucleus);

(2) The compound obtained in (1) (470 mg) is dissolved in 1.1 ml offormic acid. With ice cooling, 2.8 ml of 1.4M hydrochloric acid solutionin dioxane is added. The mixture is stirred at room temperature for 30minutes. The reaction mixture is poured into isopropyl ether and theprecipitate is collected by filtration to give 351 mg of diethylL-lysylcromoglycate dihydrochloride (yield 88%).

IR (KBr, cm⁻¹) 1740

NMR (DMSO-d₆, δ ppm): 1.34 (6H, t, J=7 Hz, --CH₂ CH₃); 1.4˜2.2 (6H, m,--(CH₂)₃ --); 2.3˜3.0 (2H, m, --CH₂ NH₃ ⁺); 3.7˜4.2 (1H, m, ##STR8##4.36 (4H, q, J=7 Hz, --CH₂ CH₃); 4.3˜4.9 (4H, m, ##STR9## 5.4˜5.9 (1H,m, ##STR10## 6.72, 6.74 (2H, s, --H in position 3 of chromone nucleus);7.12, 7.19 (4H, d, J=9 Hz, --H in position 6 and in position 8 ofchromone nucleus); 7.74 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus); 7.5˜9.0 (6H, br, -NH₃ ⁺)

EXAMPLE 2 Synthesis of diethyl glycylcromoglycate hydrochloride

Using BOC-glycine and proceeding in the same manner as in Example 1,there is obtained diethyl glycylcromoglycate hydrochloirde.

IR (KBr, cm⁻¹) 1740, 1650

NMR (DMSO-d₆, δ ppm): 1.34 (6H, t, J=7 Hz, --CH₂ CH₃); 3.84 (2H, br.s,--CH₂ NH₃ ⁺); 4.38 (4H, q, J=7 Hz, --CH₂ CH₃); 4.49˜4.87 (4H, m,##STR11## 5.49-5.89 (1H, m, ##STR12## 6.69 (2H, s, --H in position 3 ofchromone nucleus); 6.95˜7.38 (4H, m, --H in position 6 and in position 8of chromone nucleus); 7.72 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus); 8.2˜9.5 (3H, br, --NH₃ ⁺)

EXAMPLE 3 Synthesis of dimethyl L-alanylcromoglycate hydrochloride

Using dimethyl cromoglycate and BOC-L-alanine and proceeding in the samemanner as in Example 1, there is obtained dimethyl L-alanylcromoglycatehydrochloride.

IR (nujol, cm⁻¹) 1745

NMR (DMSO-d₆, δ ppm): 1.43 (3H, d, J=8 Hz, ##STR13## 3.92 (6H, s,--OCH₃); 4.10 (1H, q, J=8 Hz, ##STR14## 4.4˜4.8 (4H, br, ##STR15##5.4˜5.8 (1H, br, ##STR16## 6.70, 6.74 (2H, s, --H in position 3 ofchromone nucleus); 7.08, 7.20 (4H, d, J=9 Hz, --H in position 6 and inposition 8 of chromone nucleus); 7.74 (2H, t, J=9 Hz, --H in position of7 of chromone nucleus); 8.3-8.9 (3H, br, --NH₃ ⁺)

EXAMPLE 4 Synthesis of diethyl L-alanylcromoglycate hydrochloride

Using BOC-L-alanine and proceeding in the same manner as in Example 1,there is obtained diethyl L-alanylcromoglycate hydrochloride.

IR (KBr, cm³¹ 1) 1740

NMR (DMSO-d₆, δ ppm): 1.34 (6H, t, J=7 Hz, --CH₂ CH₃); 1.46 (3H, d, J=8Hz, ##STR17## 3.9˜4.5 (1H, m, ##STR18## 4.36 (4H, q, J=7 Hz, --CH₂ C₃);4.3˜4.8 (4H, m, ##STR19## 5.3˜5.9 (1H, m, ##STR20## 6.69, 6.71 (2H, s,--H in position 3 of chromone nucleus); 7.06, 7.21 (4H, d, J=9 Hz, --Hin position 6 and in position 8of chromone nucleus); 7.73 (2H, t J=9 Hz,--H in position 7 of chromone nucleus); 8.0˜9.0 (3H, br, --NH₃ ⁺)

EXAMPLE 5 Synthesis of diethyl β-alanylcromoglycate hydrochloride

Using BOC-β-alanine and proceeding in the same manner as in Example 1,there is obtained diethyl β-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1740, 1650

NMR (DMSO-d₆, δ ppm): 1.34 (6H, t, J=7 Hz, --CH₂ CH₃ --); 2.7˜3.2 (4H,m, --CH₂ CH₂ --); 4.37 (4H, q, J=7 Hz, --CH₂ CH₃); 4.52 (4H, br.s,##STR21## 5.4˜5.75 (1H, br, ##STR22## 6.70 (2H, s, --H in position 3 ofchromone nucleus); 6.9˜7.35 (4H, m, --H in position 6 and in position 8of chromone nucleus); 7.72 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus); 7.9˜8.4 (3H, br, --NH₃ ⁺).

EXAMPLE 6 Synthesis of diethyl N-glycylglycylcromoglycate hydrochloride

Using N-(BOC-glycyl)glycine and proceeding in the same manner as inExample 1, there is obtained diethyl N-glycylglycylcromoglycatehydrochloride.

IR (KBr, cm⁻¹) 1740, 1690, 1650

NMR (DMSO-d₆, δ ppm): 1.34 (6H, t, J=7 Hz, --CH₂ CH₃); 3.5˜5.0 (12H, m,##STR23## --CH₂ CH₃, --CH₂ NHCOCH₂ --); 5.2˜5.9 (1H, m, ##STR24## 6.69(2H, s, --H in position 3 of chromone nucleus); 7.08, 7.17 (4H, d, J=9Hz, --H in position 6 and in position 8 of chromone nucleus); 7.72 (2H,t, J=9 Hz, --H in position 7 of chromone nucleus); 7.7˜8.7 (3H, m, --NH₃⁺); 8.5˜9.2 (1H, m, --NH--);

EXAMPLE 7 Synthesis of diethyl N-(L-alanyl)glycylcromoglycatehydrochloride

Using N-(BOC-L-alanyl)glycine and proceeding in the same manner as inExample 1, there is obtained diethyl N-(L-alanyl)glycylcromoglycatehydrochloride.

IR (KBr, cm⁻¹) 1740, 1650

NMR (DMSO-d₆, δ ppm): 1.34 (6H, t J=7 Hz, --CH₂ CH₃); 1.40 (3H, d, J=8Hz, ##STR25## 3.6˜4.3 (3H, m, --COCH₂ NH--, ##STR26## 4.38 (4H, q, J=7Hz, --CH₂ CH₃); 4.2˜4.8 (4H, m, ##STR27## 5.2˜5.8 (1H, m, ##STR28## 6.68(2H, s, --H in position 3 of chromone nucleus); 7.06, 7.18 (4H, d, J=9Hz, --H in position 6 and in position 8 of chromone nucleus); 7.71 (2H,t, J=9 Hz, --H in position 7 of chromone nucleus); 7.9, 8.6 (3H, m,--NH₃ ⁺); 8.6˜9.1 (1H, m, --NH--)

EXAMPLE 8 Synthesis of diethyl N-(L-leucyl)glycylcromoglycatehydrochloride

Using N-(BOC-L-leucyl)glycine and proceeding in the same manner as inExample 1, there is obtained diethyl N-(L-leucyl)glycylcromoglycatehydrochloride.

IR (KBr, cm⁻¹) 1740, 1655

NMR (DMSO-d₆, δ ppm): 0.89 (6H, d, J=5 Hz, CH(CH₃)₂); 1.35 (6H, t, J=7Hz, --CH₂ CH₃); 1.3˜2.1 (3H, m, ##STR29## 3.6˜4.3 (3H, m, --NHCH₂ CO--,##STR30## 4.38 (4H, q, J=7 Hz, --CH₂ CH₃); 4.3˜4.9 (4H, m, ##STR31##5.3˜5.8 (1H, br, ##STR32## 6.68 (2H, s, --H in position 6 of chromonenucleus); 7.06, 7.17 (4H, d, J=9 Hz, --H in position 3 and in position 8of chromone nucleus); 7.71 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus); 7.9˜8.6 (3H, m, --NH₃ ⁺); 8.7˜9.2 (1H, m, --NH--);

EXAMPLE 9 Synthesis of diethyl L-valylcromoglycate hydrochloride

Using BOC-L-valine and proceeding in the same manner as in Example 1,there is obtained diethyl L-valylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1735, 1650:

NMR (DMSO-d₆, δ ppm): 0.92 (6H, d, J=7 Hz, --CH(CH₃)₂); 1.34 (6H, t J=7Hz, --CH₂ CH₃); 1.81˜2.31 (1H, m, --CH(CH₃)₂); 3.81˜4.05 (1H, m,##STR33## 4.38 (4H, q, J=7 Hz, -CH₂ CH₃); 4.48˜4.73 (4H, m, ##STR34##5.5˜5.86 (1H, m, ##STR35## 6.71˜7.91 (8H, m, --H in position 3, inposition 6, in position 7 and in position 8 of chromone nucleus);8.32˜8.83 (3H, br, --NH₃ ⁺);

EXAMPLE 10 Synthesis of diethyl L-leucylcromoglycate hydrochloride

Using BOC-L-leucine and proceeding in the same manner as in Example 1,there is obtained diethyl L-leucylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1740, 1650:

NMR (DMSO-d₆, δ ppm): 0.76 (6H, m, --CH(CH₃)₂); 1.34 (6H, t, J=7 Hz,--CH₂ CH₃); 1.51˜1.96 (3H, m, --CH₂ CH(CH₃)₂); 3.93˜4.04 (1H, m,##STR36## 4.39 (4H, q, J=7 Hz, --CH₂ CH₃); 4.49˜4.83 (4H, m, ##STR37##5.44˜5.83 (1H, m, ##STR38## 6.72˜7.92 (8H, m, --H in position 3, inposition 6, in position 7 and in position 8 of chromone nucleus);8.27˜9.03 (3H, br, --NH₃ ⁺)

EXAMPLE 11 Synthesis of di(2-ethoxyethyl) L-lysylcromoglycatedihydrochloride

(1) To a mixture of 3 ml of triethylamine and 20 ml of DMF, there areadded 3 ml of 2-ethoxyethyl bromide and 4 g of DSCG and the mixture isstirred at 90° C. for 3 hours. To the reaction mixture, there are added200 ml of water and 50 ml of ethyl acetate. The organic layer isseparated, washed with aqueous sodium bicarbonate solution and aqueoussodium chloride solution, and dried over sodium sulfate. After removalof the solvent by distillation, the residue is purified by silica gelcolumn chromatography to give 2.6 g of di(2-ethoxyethyl) cromoglycate(yield 50%).

IR (KBr, cm⁻¹) 3400, 1745, 1730, 1650:

NMR (CDCl₃, δ ppm): 1.23 (6H, t, J=7 Hz, --CH₂ CH₃); 2.6˜3.5 (1H, br,--OH); 3.57 (4H, q, J=7 Hz, --CH₂ CH₃); 3.74 (4H, t, J=5 Hz, --CO₂ CH₂CH₂ --); 4.1˜4.8 (5H, m, ##STR39## 4.50 (4H, t, J=5 Hz, --CO₂ CH₂ --);6.8˜7.4 (6H, --H in position 3, in position 6 and in position 8 ofchromone nucleus); 7.58 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus)

(2) Using diBOC-L-lysine and proceeding in the same manner as in Example1, there is obtained di(2-ethoxyethyl) L-lysylcromoglycatedihydrochloride.

IR (KBr, cm⁻¹) 3450, 1745:

NMR (DMSO-d₆, δ ppm): 1.14 (6H, t, J=7 Hz, --CH_(2LL) CH₃); 1.2˜2.1 (6H,m, --(CH₂)₃ --); 2.4˜2.9 (2H, m, --CH₂ NH₃ ⁺); 3.52 (4H, q, J=7 Hz,--CH₂ CH₃ --); 3.4˜4.0 (4H, m, --CH₂ CH₂ O--); 3.8˜4.2 (1H, m, ##STR40##4.0˜5.0 (8H, m, ##STR41## --CO₂ CH₂ --); 5.4˜5.9 (1H, m, ##STR42##6.73˜6.75 (2H, s, --H in position 3 of chromone nucleus); 6.9˜7.4 (4H,m, --H in position 6 and in position 8 of chromone nucleus); 7.76 (2H,t, J=9 Hz, --H in position 7 of chromone nucleus); 7.4˜9.5 (6H, m, --NH₃⁺)

EXAMPLE 12 Synthesis of di(2-ethoxyethyl) L-alanylcromoglycatehydrochloride

Proceeding in the same manner as in Example 11, there is obtaineddi(2-ethoxyethyl) L-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1745, 1655:

NMR (DMSO-d₆, δ ppm): 1.14 (6H, t, J=7 Hz, --CH₂ CH₃); 1.43 (3H, d, J=8Hz, ##STR43## 3.52 (4H, q, J=7 Hz, --CH₂ CH₃); 3.5˜4.0 (4H, m, --CH₂ CH₂O); 4.05 (1H, m, ##STR44## 4.1˜4.9 (8H, m., ##STR45## --CO₂ CH₂ --);5.3˜5.9 (1H, m, ##STR46## 6.7˜6.73 (2H, s, --H in position 3 of chromonenucleus); 6.9˜7.4 (4H, m, --H in position 6 and in position 8 ofchromone nucleus); 7.75 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus); 8.0˜9.0 (3H, br, --NH₃ ⁺)

EXAMPLE 13 Synthesis of di(2-ethoxyethyl) N-(L-alanyl)glycylcromoglycatehydrochloride

Using N-(BOC-L-alanyl)glycine and proceeding in the same manner as inExample 11, there is obtained di(2-ethoxyethyl)N-(L-alanyl)glycylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1735, 1720, 1650:

NMR (DMSO-d₆, δ ppm): 1.13 (6H, t, J=7 Hz, --CH₂ CH₃); 1.37 (3H, d, J=8Hz, ##STR47## 3.5 (4H, q, J=7 Hz, --CH₂ CH₃); 3.5˜3.9 (4H, m, --CH₂ CH₂O--); 3.8˜4.2 (3H, m, ##STR48## --CH₂ NH); 4.1˜4.9 (8H, m, ##STR49##--CO₂ CH₂ --); 5.3˜5.8 (1H, m, ##STR50## 6.7 (2H, s, --H in position 3of chromone nucleus); 7.08, 7.17 (4H, d, J=9 Hz, --H in position 6 andin position 8 of chromone nucleus); 7.72 (2H, t, J=9 Hz, --H in position7of chromone nucleus); 7.5˜8.5 (3H, br, --NH₃ ⁺); 8.6˜9.1 (1H, br,--NHCO--)

EXAMPLE 14 Synthesis of di(pivaloyloxymethyl) L-lysylcromoglycatedihydrochloride

(1) After Di(pivaloyloxymethyl) cromoglycate (500 mg) is dissolved in 4ml of methylene chloride, 370 mg of diBOC-L-lysine is added, and then 14mg of dimethylaminopyridine is added and furthermore 1.8 ml of 1M DCCsolution in methylene chloride is added dropwise at 0° C. After 4 hoursof stirring, the precipitate urea compound is filtered off and thefiltrate residue is purified by silica gel column chromatography to give710 mg of di(pivaloyloxymethyl) diBOC-L-lysylcromoglycate (yield 97%).

IR (nujol, cm⁻¹) 1755, 1710, 1655:

NMR (CDCl₃, δ ppm): 1.36 (18H, s, (CH₃)₃ CCO); 1.41, 1.43 (18H, s, BOC);1.6˜2.1 (4.0˜4.4 (1H, m, ##STR51## 4.60 (4H, br, ##STR52## 5.1˜5.4 (2H,br, --NH--); 5.5˜5.8 (1H, m, ##STR53## ; 5.98 (4H, s, --OCH₂ O--); 6.90(2H, s, --H in position 3 of chromone nucleus); 6.98, 7.12 (4H, d, J=9Hz, --H in position 6 and in position 8 of chromone nucleus); 7.62 (2H,t, J=9 Hz, --H in position 7 of chromone nucleus)

(2) The compound obtained in 1) (400 mg) is dissolved in 0.8 ml offormic acid, then 2 ml of 1.4M hydrogen chloride solution in dioxane isadded, and the mixture is stirred at room temperature for 5 minutes. Byadding isopropyl ether, there is obtained 300 mg ofdi(pivaloyloxymethyl) L-lysylcromoglycate dihydrochloride (yield 86%).

IR (nujol, cm⁻¹) 1760, 1660:

NMR (DMSO-d₆, δ ppm): 1.20 (18H, s, --C(CH₃)₃); 1.4˜2.1 (6H, br,--(CH₂)₃ --); 2.4˜3.0 (2H, m, --CH₂ NH₃ ⁺); 3.8˜4.2 (1H, m, ##STR54##4.4˜4.8 (4H, m, ##STR55## 5.5˜5.8 (1H, m, ##STR56## 5.98 (4H, s, --OCH₂O--); 6.77, 6.78 (2H, s, --H in position 3 of chromone nucleus); 7.10,7.20 (4H, d, J=9 Hz, --H in position 6 and in position 8 of chromonenucleus); 7.78 (2H, t, J=9 Hz, --H in position 7 of chromone nucleus);8.0˜9.2 (6H, br, --NH₃ ⁺)

EXAMPLE 15 Synthesis of di(pivaloyloxymethyl) L-alanylcromoglycatehydrochloride

Using BOC-L-alanine and proceeding in the same manner as in Example 14,there is obtained di(pivaloyloxymethyl) L-alanylcromoglycatehydrochloride.

IR (nujol, cm⁻¹) 1760, 1660:

NMR (DMSO-d₆, δ ppm): 1.19 (18H, s, --C(CH₃)₃); 1.43 (3H, d, J=8 Hz,##STR57## 4.0˜4.8 (5H, m, ##STR58## 5.3˜5.8 (1H, m, ##STR59## 5.96 (4H,s, --OCH₂ O--); 6.73 (2H, s, --H in position 3 of chromone 7.10, 7.25(4H, d, J=9 Hz, --H in position 6 and in position 8 of chromonenucleus); 7.74 (2H, t, J=9 Hz, --H in position 7 of chromone nucleus);8.2˜8.6 (3H, br, --NH₃ ⁺)

EXAMPLE 16 Synthesis of di(acetoxymethyl) β-alanylcromoglycatehydrochloride

Using di(acetoxymethyl) cromolgycate and BOC-β-alanine and proceeding inthe same manner as in Example 14, there is obtained di(acetoxymethyl)β-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1760, 1660:

NMR (DMSO-d₆, δ ppm): 2.13 (6H, s, --CH₃); 2.6˜3.3 (4H, m, --CH₂ CH₂--); 4.2˜4.9 (4H, m, ##STR60## 5.3˜5.9 (1H, m, ##STR61## 5.92 (4H, s,--OCH₂ O--); 6.72 (2H, s, --H in position 3 of chromone nucleus); 7.07,7.20 (4H, d, J=9 Hz, --H in position 6 and in position 8 of chromonenucleus); 7.73 (2H, t, J=9 Hz, --H in position 7 of chromone nucleus);7.6˜8.5 (3H, br, --NH₃ ⁺)

EXAMPLE 17 Synthesis of di(1-acetoxyethyl) N-(glycyl)glycylcromoglycatehydrochloride

(1) DSCG(6.1 g) is dissolved in 96 ml of water. After Chloroform (96 ml)and 7.5 g of benzyltri-n-butylammonium chloride are added, 4 g of1-bromoethyl acetate is added dropwise over 15 minutes, while the pH ismaintained at 6 with NaHCO₃. After 45 hours of stirring, the chloroformlayer is separated and dried over sodium sulfate. The solvent isdistilled off and the residue is purified by silica gel columnchromatography to give 4.4 g of di(1-acetoxyethyl) cromoglycate (yield58%).

IR (KBr, cm¹) 1760, 1650:

NMR (CDCl₃, δ ppm): 1.63 (6H, d, J=9 Hz, ##STR62## 2.12 (6H, s, --COCH₃)3.96 (1H, br, --OH) 4.45 (5H, m, ##STR63## 6.8˜7.35 (10H, m, --H inposition 3, in position 6 and in position 8 of chromone nucleus,##STR64## 7.6 (2H, t, J=9 Hz, --H in position 7 of chromone nucleus)

(2) After the compound obtained in 1) (780 mg) is dissolved in 8 ml ofmethylene chloride, 396 mg of N-(BOC-glycyl)glycine, 74 mg ofdimethylaminpyridine and 352 mg of DCC are added, and the mixture isstirred at 0° C. for 17 hours. The precipitated urea compound isfiltered off, and the filtrate is washed with aqueous citric acidsolution and dried over sodium sulfate. After removal of the solvent bydistillation, the residue is purified by silica gel columnchromatography to give 669 mg of di(1-acetoxyethyl)N-(BOC-glycyl)glycylcromoglycate (yield 64%).

IR (KBr, cm⁻¹) 1760, 1715, 1650:

NMR (CDCl₃, δ ppm): 1.44 (9H, s, --C(CH₃)₃); 1.63 (6H, d, J=6 Hz,##STR65## 2.12 (6H, s, --COCH₃); 3.8˜4.3 (4H, m, --CH₂ NHCOCH₂ --);4.4˜4.8 (4H, m, ##STR66## 5.2˜5.9 (3H, m, --NHCO, ##STR67## 6.8˜7.3(10H, m, ##STR68## --H in position 3, in position 6 and in position 8 ofchromone nucleus); 7.59 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus)

(3) The compound obtained in 2) (600 mg) is dissolved in 1.2 ml offormic acid and, with ice cooling, 3.6 ml of 1.3M hydrogen chloridesolution in dioxane is added. The mixture is stirred at room temperaturefor 30 minutes. The reaction mixture is poured into isopropyl ether andthe resultant precipitate is collected by filtration and dried to give492 mg of di(1-acetoxyethyl) N-(glycyl)glycylcromoglycate hydrochloride(yield 89%).

IR (KBr, cm⁻¹) 1760, 1690, 1655:

NMR (DMSO-d₆, δ ppm): 1.57 (6H, d, J=9 Hz, ##STR69## 2.10 (6H, s,--COCH₃); 3.7 ˜4.3 (4H, m, --CH₂ NHCOCH₂ --); 4.2˜4.9 (4H, m, ##STR70##5.2˜5.8 (1H, m, ##STR71## 6.73 (2H, m, --H in position 3 of chromonenucleus); 6.7˜7.4 (6H, m, --H in position 6 and in position 8 ofchromone nucleus, ##STR72## 7.72 (2H, t, J=9 Hz, --H in position 7 ofchromone nucleus); 8.6 (3H, m, --NH₃ ⁺); 8.6˜9.0 (1H, m, --NHCO--);

EXAMPLE 18 Synthesis of di(1-acetoxyethyl)N-(L-alanyl)glycylcromoglycate hydrochloride

Using N-(BOC-L-alanyl)glycine and proceeding in the same manner as inExample 17, there is obtained di(1-acetoxyethyl)N-(L-alanyl)glycylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1750, 1650:

NMR (DMSO-d₆, δ ppm): 1.36 (3H, d, J=8 Hz, ##STR73## ; 1.58 (6H, d, J=6Hz, ##STR74## 2.10 (6H, s, CH₃ CO--); 3.8˜4.2 (3H, m, --CH₂ NH--,##STR75## 4.2˜4.8 (4H, m, ##STR76## 5.3˜5.8 (1H, m, ##STR77## 6.72 (2H,s, --H in position 3 of chromone nucleus); 6.8˜7.35 (6H, m, --H inposition 6 and in position 8 of chromone nucleus, ##STR78## 7.72 (2H, t,J=9 Hz, --H in position 7 of chromone nucleus); 8.0˜8.4 (3H, br, --NH₃⁺); 8.7˜9.1 (1H, br, --NHCO--);

EXAMPLE 19 Synthesis of di(1-acetoxyethyl) L-alanylcromoglycatehydrochloride

Using BOC-L-alanine and proceeding in the same manner as in Example 17,there is obtained di(1-acetoxyethyl) L-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1760, 1655:

NMR (DMSO-d₆, δ ppm): 1.42 (3H, d, J=8 Hz, ##STR79## 1.57 (6H, d, J=6Hz, ##STR80## 2.09 (6H, s, CH₃ CO--) 4.04˜4.17 (1H, m, ##STR81##4.28˜4.8 (4H, m, ##STR82## 5.44˜5.82 (1H, m, ##STR83## 6.76˜7.92 (10H,m, --H in position 3, in position 6, in position 7 and in position 8 ofchromone nucleus, ##STR84## 8.0˜8.7 (3H, m, --NH₃ ⁺);

EXAMPLE 20 Synthesis of di(1-acetoxyethyl) β-alanylcromoglycatehydrochloride

Using BOC-β-alanine and proceeding in the same manner as in Example 17,there is obtained di(1-acetoxyethyl) β-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1760, 1655:

NMR (DMSO-d₆, δ ppm): 1.60 (6H, d, J=6 Hz, ##STR85## 2.12 (6H, s,--COCH₃); 2.7˜3.35 (4H, m, --CH₂ CH₂ --); 4.3˜4.85 (4H, m, ##STR86##5.4˜5.8 (1H, m, ##STR87## 6.74 (2H, s, --H in position 3 of chromonenucleus); 6.7˜7.4 (6H, m. --H in position 6 and in position 8 ofchromone nucleus, ##STR88## 7.23 (2H, t, J=9 Hz, --H in position 7 ofchromone nucleus); 7.9˜8.4 (3H, br, --NH₃ ⁺)

EXAMPLE 21 Synthesis of di(1-acetoxyethyl) L-lysylcromoglycatedihydrochloride

Using di-BOC-L-lysine and proceeding in the same manner as in Example17, there is obtained di(1-acetoxyethyl) L-lysylcromoglycatedihydrochloride.

IR (KBr, cm⁻¹) 1770, 1660:

NMR (DMSO-d₆, δ ppm): 1.58 (6H, d, J=6 Hz, ##STR89## 1.2˜2.0 (6H, m,--(CH₂)₃ --); 2.10 (6H, s, CH₃ CO--); 2.4˜2.8 (2H, m, --CH₂ NH₃ ⁺);3.9˜4.2 (1H, m, ##STR90## 4.43˜4.85 (4H, m, ##STR91## 5.48˜5.91 (1H, m,##STR92## 6.75˜7.45 (8H, m, --H in position 3, in position 6 and inposition 8 of chromone nucleus, ##STR93## 7.75 (2H, t, J=9 Hz, --H inposition 7 of chromone nucleus) 7.5˜9.1 (6H, br, --NH₃ ⁺)

EXAMPLE 22 Synthesis of di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)L-α-aspartylcromoglycate dihydrochloride

(1) After DSCG(1 g) is dissolved in 40 ml of DMF, 0.91 g of4-bromomethyl-5-methyl-1,3-dioxol-2-one is added, and the mixture isstirred at 40° C. for 2 hours. Water (400 ml) is added and the mixtureis extracted with methylene chloride. The extract is washed with waterand dried, and the solvent is distilled off to give 1.0 g ofdi(5-methyl-2-on-1,3-dioxol-4-ylmethyl) cromoglycate (yield 80%).

IR (nujol, cm⁻¹)1825, 1750:

NMR (DMSO-d₆, δ ppm): 2.22 (6H, s, dioxole--CH₃); 4.32 (5H, s, ##STR94##5.26 (6H, s, dioxole--CH₂ --, --OH); 6.73 (2H, s, --H in position 3 ofchromone nucleus); 6.87-7.33 (4H, m, --H in position 6 and in position 8of chromone nucleus); 7.71 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus);

(2) The compound obtained in (1) (1.0 g) is dissolved in 10 ml ofmethylene chloride. To the solution are added 531 mg of β-t-butylBOC-L-asparatate and 88 mg of dimethylaminopyridine and, after furtheraddition of 417 mg of DCC, the mixture is stirred at 0° C. for 5 hours.After the precipitated urea compound is filtered off, the solvent isdistilled off and ethyl acetate is added to the residue. The resultantsolution is washed with aqueous citric acid solution and then withaqueous sodium chloride solution and dried over sodium sulfate. Afterremoval of the solvent by distillation, the residue is purified bysilica gel column chromatography to give 625 mg ofdi(5-methyl-2-on-1,3-dioxol-4-ylmethyl)N-BOC-β-t-butyl-L-aspartylcromoglycate (yield 45%).

IR (KBr, cm⁻¹) 1820, 1745, 1720, 1655:

NMR (CDCl₃, δ ppm): 1.36, 1.42 (18H, s, --C(CH₃)₃); 1.5˜1.8 (1H, br,--NH--) 2.24 (6H, s, dioxole--CH); 2.7˜3.0 (2H, d, J=5 Hz, --CH₂ CO₂--); 4.3˜4.9 (4H, m, ##STR95## 5.10 (4H, s, dioxole--CH₂ --); 5.2˜6.0(2H, m 6.85 (2H, s, --H in position 3 of chromone nucleus); 6.8˜7.3 (4H,m, --H in position 6 and in position 8 of chromone nucleus); 7.57 (2H,t, J=9 Hz, --H in position 7 of chromone nucleus)

(3) The compound obtained in (2) (377 mg) is dissolved in 0.8 ml offormic acid and, with ice cooling, 2 ml of 1.4M hydrogen chloridesolution in dioxane is added. The mixture is stirred at room temperaturefor 20 hours. The reaction mixture is poured into isopropyl ether togive 379 mg of di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)L-α-aspartylcromoglycate hydrochloride (yield 95%).

IR (KBr, cm⁻¹) 1820, 1750, 1655:

NMR (DMSO-d₆, δ ppm): 2.22 (6H, s, dioxole--CH₃); 2.6˜3.3 (2H, m, --CH₂CO₂ --); 4.1˜4.6 (1H, m, ##STR96## 4.2˜4.9 (4H, br, ##STR97## 5.27 (4H,s, dioxole--CH₂ --); 5.3˜5.9 (1H, br, ##STR98## 6.75 (2H, s, --H inposition 3 of chromone nucleus); 6.95˜7.35 (4H, m, --H in position 6 andin position 8 of chromone nucleus); 7.76 (2H, t, J=9 Hz, --H in position7 of chromone nucleus); 7.0˜10 (4H, br, --COOH, --NH₃ ⁺)

EXAMPLE 23 Synthesis ofdi(5-methyl-2-on-1,3-dioxol-4-ylmethyl)glycylcromoglycate hydrochloride

Using BOC-glycine and proceeding in the same manner as in Example 22,there is obtained di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)glycylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1815, 1745, 1645:

NMR (DMSO-d₆, δ ppm): 2.22 (6H, s, dioxole--CH₃); 3.83 (2H, s, --CH₂ NH₃⁺); 4.57 (4H, br.s, ##STR99## 5.25 (4H, s, dioxole--CH₂ --); 5.4˜5.95(1H, br, ##STR100## 6.74 (2H, s, --H in position 3 of chromone nucleus);6.9˜7.38 (4H, m, --H in position 6 and in position 8 of chromonenucleus); 7.73 (2H, t, J=9 Hz, --H in position 7 of chromone nucleus);8.0˜8.9 (3H, br, --NH₃ ⁺)

EXAMPLE 24 Synthesis of di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)L-alanylcromoglycate hydrochloride

Using BOC-alanine and proceeding in the same manner as in Example 22,there is obtained di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)L-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1815, 1740, 1650:

NMR (DMSO-d₆, δ ppm): 1.42 (3H, d, J=8 Hz, ##STR101## 2.21 (6H, s,dioxole--CH₃); 4.1 (1H, q, ##STR102## 4.58 (4H, br.s, ##STR103## 5.27(4H, s, dioxole--CH₂ --); 5.4˜5.85 (1H, br, ##STR104## 6.74, 6.77 (2H,s, --H in position 3 of chromone nucleus); 6.9˜7.4 (4H, m, --H inposition 6 and in position 8 of chromone nucleus); 7.73 (2H, t, J=9 Hz,--H in position 7 of chromone nucleus); 8.15˜8.9 (3H, br, --NH₃ ⁺)

EXAMPLE 25 Synthesis of di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)β-alanylcromoglycate hydrochloride

Using BOC-β-alanine and proceeding in the same manner as in Example 22,there is obtained di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)β-alanylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1815, 1740, 1650:

NMR (DMSO-d₆, δ ppm): 2.22 (6H, s, dioxole--CH₃); 2.65˜3.3 (4H, m, --CH₂CH₂ --); 4.55 (4H, br.s, ##STR105## 5.27 (4H, s, dioxole--CH₂ --);5.3˜5.8 (1H, br, ##STR106## 6.73 (2H, s, --H in position 3 of chromonenucleus); 6.85˜7.4 (4H, m, --H in position 6 and in position 8 ofchromone nucleus); 7.73 (2H, t, J=9 Hz, --H in position 7 of chromonenucleus); 7.7˜8.45 (3H, br, --NH₃ ⁺)

EXAMPLE 26 Synthesis of di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)L-prolylcromoglycate hydrochloride

Using BOC-L-proline and proceeding in the same manner as in Example 22,there is obtained di(5-methyl-2-on-1,3-dioxol-4-ylmethyl)L-prolylcromoglycate hydrochloride.

IR (KBr, cm⁻¹) 1815, 1740, 1650:

NMR (DMSO-d₆, δ ppm): 1.5˜2.7 (4H, m, --H₂ in position 3 and in position4 of pyrrole ring) 2.23 (6H, s, dioxole--CH₃) 3.0-3.7 (2H, m, --H₂ inposition 5 of pyrrole ring) 4.1˜4.9 (5H, m, ##STR107## --H in position 2of pyrrole ring) 5.25 (4H, s, dioxole--CH₂ --) 5.4˜5.9 (1H, br,##STR108## 6.74, 6.76 (2H, s, --H in position 3 of chromone nucleus);6.85˜7.4 (4H, m, --H in position 6 and in position 8 of chromonenucleus); 7.73 (2H, t, J=9 Hz, --H in position 7 of chromone nucleus);8.6˜10.4 (2H, br, ##STR109##

EXAMPLE 27 Synthesis of di(1-ethoxycarbonyloxyethyl)β-alanylcromoglycate hydrochloride

(1) DSCG (0.5 g) is added to 20 ml of DMF and, with ice cooling, 2 g of1-iodoethyl carbonate is added dropwise over 2 hours. After further 2hours of stirring, the reaction mixture is poured into 200 ml of waterand extracted with ethyl acetate. The extract is washed with water anddried over sodium sulfate, and the solvent is then distilled off to give256 mg of di(1-ethoxycarbonyloxyethyl) cromoglycate (yield 38%).

IR (nujol, cm⁻¹) 1765, 1660:

NMR (CDCl₃, δ ppm): 1.33 (6H, t, J=7 Hz, --CH₂ CH₃); 1.67 (6H, d, J=6Hz, ##STR110## ; 2.5˜3.7 (1H, br, --OH); 4.24 (4H, q, J=7 Hz, --CH₂CH₃); 4.1˜4.8 (5H, m, ##STR111## 6.75-7.35 (8H, m, --H in position 3, inposition 6 and in position 8 of chromone nucleus); 7.59 (2H, t, J=9 Hz,--H in position 7 of chromone nucleus);

(2) The compound obtained in (1) is treated in the same manner as inExample 14 to give di(1-ethoxycarbonyloxyethyl) β-alanylcromoglycatehydrochloride.

IR (KBr, cm⁻¹) 1755, 1650:

NMR (DMSO-d₆, δ ppm): 1.25 (6H, t, J=7 Hz, --CH₂ CH₃); 1.66 (6H, d, J=6Hz, ##STR112## 2.5˜3.4 (4H, m, --CH₂ CH₂ --); 4.18 (4H, q, J=7 Hz, --CH₂CH₃); 4.55 (4H, br, ##STR113## 5.35˜5.85 (1H, m, ##STR114## 6.75 (2H, s,--H in position 3 of chromone nucleus); 6.8-7.35 (6H, m, ##STR115## --Hin position 6 and in position 8 of chromone nucleus; 7.71 (2H, t, J=9Hz, --H in position 7 of chromone nucleus) 7.5˜8.5 (2H, br, --NH₃ ⁺)

Acute toxicity test

The cromoglycic acid derivatives produced in Examples 1, 4, 7, 11 and 12were administered, each in the form of an aqueous solution, to groups ofthree ICR-strain male mice by the oral route. The results thus obtainedare shown below in Table 1.

                  TABLE 1                                                         ______________________________________                                        Example No. in which the                                                      compound was produced                                                                           LD.sub.50 (mg/kg)                                           ______________________________________                                        Example 1         >1,000                                                      Example 4         >1,000                                                      Example 7         >1,000                                                      Example 11        >1,000                                                      Example 12        >1,000                                                      ______________________________________                                    

Dosage Form Example 1

Tablets having the following composition were produced in theconventional manner.

Compound of Example 1: 5 mg

Polyvinylpyrrolidone: 20 mg

Starch: 75 mg

Magnesium stearate: 2 mg

Dosage Form Example 2

Tablets having the following composition were produced in theconventional manner.

Compound of Example 1: 10 mg

Tartaric acid: 50 mg

Starch: 50 mg

Magnesium stearate: 3 mg

Dosage Form Examples 3

Tablets having the following composition were produced in theconventional manner.

Compound of Example 4: 20 mg

Starch: 50 mg

Hydroxypropylcellulose: 3 mg

Magnesium stearate: 5 mg

Dosage Form Example 4

The compound of Example 9 was admixed with citric acid and capsules wereproduced by using an ordinary capsule filling technique.

Compound of Example 9: 100 mg

Citric acid: 25 mg

Magnesium stearate: 1 mg

Dosage Form Example 5

Capsules having the following composition were produced in the samemanner as in Dosage Form Example 4.

Compound of Example 1: 20 mg

Magnesium stearate: 2 mg

Lactose: To make the total weight 100 mg

Dosage Form Example 6

Dry syrup was produced in accordance with the following formulation.

Compound of Example 12: 50 mg

Citric acid: 25 mg

Sucrose: 70 mg

CMC-Na: 20 mg

The compounds according to the invention were orally administered torabbit in the form of an aqueous solution or suspension at a dose of 5mg/kg and the urinary recovery rates (based on the correspondingquantities of cromoglycic acid) were determined by HPLC. The resultsobtained are shown below in Table 2.

                  TABLE 2                                                         ______________________________________                                                      0-6 Hr urinary                                                                recovery (%)                                                    ______________________________________                                        Cromoglycic acid                                                                              3.5                                                           Example 1       32.6                                                          Example 4       20.2                                                          Example 7       21.4                                                          Example 11      25.4                                                          Example 12      21.8                                                          ______________________________________                                    

We claim:
 1. A pharmacologically acceptable cromoglycic acid derivativeof the general formula (I): ##STR116## wherein R¹ is an α, β- or γ-aminoacid residue (for ester bonding) whose amino group is optionallysubstituted by at least one lower alkyl group, and each of R² and R³ isindependently, a lower alkyloxy-substituted or an unsubstituted loweralkyl group, a 1-alkanoyloxyalkyl group, a 1-alkoxycarbonyloxyalkylgroup, a phthalidyl group or a 5-methyl-1,3-dioxol-2-on-4-ylmethylgroup; or a nontoxic salt thereof.
 2. A cromoglycic acid derivative or anontoxic salt thereof as claimed in claim 1, wherein the amino acidresidue is lysyl, glycyl, alanyl, valyl or leucyl.
 3. A cromoglycic acidderivative or a nontoxic salt thereof as claimed in claim 1, whereineach of R² and R³ is methyl, ethyl, ethoxyethyl or 1-acetoxyethyl.
 4. Acromoglycic acid derivative or a nontoxic salt thereof as claimed inclaim 1, which is diethyl L-lysylcromoglycate dihydrochloride, diethylglycylcromoglycate hydrochloride, diethy L-alanylcromoglycatehydrochloride or di(2-ethoxyethyl) L-lysylcromoglycate dihydrochloride.5. A pharmaceutical anti-allergic composition which comprises atherapeutically effective amount of a cromoglycic acid derivative or anontoxic salt thereof as claimed in claim 1 and pharmaceuticallyacceptable additive.
 6. A method of increasing absorbability ofcromoglycic acid through the digestive tract of a host in need of suchtherapy which comprises orally administering an antiallergic-effectiveamount of a compound of claim 1 to the host.
 7. A method of increasingabsorbability of cromoglycic acid through the digestive tract whichcomprises preparing a compound of claim
 1. 8. A method for treating anallergic disease in a host afflicted with such disease, which comprisesorally administering an effective amount of a compound of claim 1 to thehost.